Outline

Objective: Cerebral cavernous malformations (CCM) are frequently caused by autosomal dominant mutations in three genes, CCM1, CCM2, and CCM3. A mutation detection rate of 94% is achieved for familial CCM if DNA- and RNA-based screening techniques are used (Denier et al., 2006). At least 57% of isolated cases with multiple lesions but negative family history also harbour detectable mutations in CCM1, CCM2, and CCM3. One likely explanation for the lack of detectable mutations in the remaining patients is the existence of large genomic rearrangements which escape exon-by-exon sequencing.

Methods: We have applied the multiplex ligation-dependent probe amplification (MLPA) technique which permits the detection of such large genomic rearrangements. While direct sequencing did not reveal a mutation in the 8-year-old index case with multiple CCMs, MLPA analyses detected a large deletion involving the entire CCM1 gene in the proband and affected members of the German CCM family.

Results: The proband had experienced a generalized tonic-clonic seizure with Todd’s paralysis and headaches at the age of five. ((Magnetic resonance imaging (MRI) of the brain showed multiple cavernous angiomas including a right temporomesial lesion that was the most likely cause of the epilepsy as determined by preoperative EEG investigation. This symptomatic lesion with a diameter of 3,5 cm was completely excised microsurgically via a pterional approach. The postoperative course of the patient was uneventful with no further epileptic events. After six months, he did not require further antiepileptic medication.)) The paternal grandfather had multiple intracranial lesions and fatal hemorrhage at age 47. The patient’s father and one aunt are clinically unaffected carriers of multiple small CCMs that did not require surgical intervention so far. Thus, deletion of the entire CCM1 gene is associated with the same intrafamilial phenotypic variability that has been observed for patients with point mutations.

Conclusions: The combination of direct sequencing and MLPA analyses enabled us a mutation detection rate of 100% for inherited cases. An up-to-date overview of all our mutations will be presented.